Acute lung injury (ALI) and chronic lung disease are together the third leading cause of death in the United States, in part due to our incomplete understanding of the mechanisms that govern injury responses in the lung. Extracellular adenosine is generated following hypoxia, and serves to orchestrate tissue responses to injury by engaging adenosine receptors. This pathway is known as the hypoxic adenosine response. Our findings suggest that adenosine serves beneficial functions on features of ALI such as the maintenance of barrier function and the dampening of inflammation. In contrast, adenosine contributes to chronic lung injury by promoting fibrosis and the development of pulmonary hypertension secondary to fibrosis. Furthermore, our findings suggest that the AD0RA2B adenosine receptor regulates both the beneficial and detrimental aspects of adenosine in the lung. The goal of this Project is to better understand the mechanisms involved in adenosine-mediated protection during ALI and its role in disease progression in order to advance adenosine-based therapies for the treatment of lung disease. We have recently gained insight into two pathways that provide information on the differential roles of adenosine in lung disease. First, we show that the equilabrative nucleoside transporter 2 (ENT2) is down regulated during both acute and chronic lung injury. ENTs are critical regulators of extracellular adenosine and we hypothesize that their regulation is involved in adenosine's protective effects during ALI and it's harmful effects during chronic disease stages. Secondly, we show the emergence of AD0RA2B-dependent responses on alternately activated macrophages (AAMs) during chronic disease stages. These specialized macrophages contribute to chronic disease progression, and we hypothesize that AAMs contribute to the stage selective responses to adenosine that promote pulmonary fibrosis and pulmonary hypertension. Four specific aims are designed to address these hypotheses and determine their significance towards human lung disease: Aim 1. Examine the beneficial roles of adenosine in ALI, Aim 2. Examine alterations in the hypoxic adenosine response during disease progression; Aim 3. Examine detrimental roles of adenosine in pulmonary hypertension secondary to fibrosis, and Aim 4. Examine the hypoxic adenosine response in patients with acute and chronic lung disease. Successful completion of this study will help promote the use of adenosine-based therapies for the treatment of lung disease.